CL387626 exhibits marked and unusual antiviral activity against respiratory syncytial virus in tissue culture and in cotton rats

Wyde, Philip R.; Moore-Poveda, Donna K.; O’Hara, Brian J.; Ding, Weidong; Mitsner, B. I.; Gilbert, Brian E.

doi:10.1016/s0166-3542(98)00002-3

Cited by 37 publications

(27 citation statements)

References 14 publications

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“…Interestingly, similar findings were obtained for RFI-641 (CL387626), another small-molecule RSV fusion inhibition that targets the F protein (3,10,12). Although it was effective when administered intranasally to cotton rats 1 h prior to virus inoculation, there was no demonstrable therapeutic effect by RFI-641 when administered postinfection in this small animal model (40). However, evidence for the therapeutic efficacy of RFI-641 against RSV was obtained in studies with experimentally infected African green monkeys, whereby intranasal administration of this compound at 12 and 24 h postinfection reduced viral titers in both nasal and throat washings (18).…”

Section: Discussionsupporting

confidence: 74%

Oral Efficacy of a Respiratory Syncytial Virus Inhibitor in Rodent Models of Infection

Cianci

Genovesi

Lamb

et al. 2004

Antimicrob Agents Chemother

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). In this report, the in vivo efficacy of BMS-433771 against RSV was further examined in the BALB/c mouse and cotton rat host models of infection. By using the Long strain of RSV, prophylactic efficacy via oral dosing was observed in both animal models. A single oral dose, administered 1 h prior to intranasal RSV inoculation, was as effective against infection as a 4-day b.i.d. dosing regimen in which the first oral dose was given 1 h prior to virus inoculation. Results of dose titration experiments suggested that RSV infection was more sensitive to inhibition by BMS-433771 treatment in the BALB/c mouse host than in the cotton rat. This was reflected by the pharmacokinetic and pharmacodynamic analysis of the efficacy data, where the area under the concentration-time curve required to achieve 50% of the maximum response was ϳ7.5-fold less for mice than for cotton rats. Inhibition of RSV by BMS-433771 in the mouse is the result of F1-mediated inhibition, as shown by the fact that a virus selected for resistance to BMS-433771 in vitro and containing a single amino acid change in the F1 region was also refractory to treatment in the mouse host. BMS-433771 efficacy against RSV infection was also demonstrated for mice that were chemically immunosuppressed by cyclophosphamide treatment, indicating that compound inhibition of the virus did not require an active host immune response.

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Section: Discussionsupporting

confidence: 74%

Oral Efficacy of a Respiratory Syncytial Virus Inhibitor in Rodent Models of Infection

Cianci

Genovesi

Lamb

et al. 2004

Antimicrob Agents Chemother

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“…The results presented here for TMC353121 in therapeutic regimens (study 2; table 1) demonstrate that the drug is able to reduce viral replication when administered 2 days after RSV challenge, confirming that sustained viral replication does occur in this murine model and can be inhibited even by delayed drug administration. In comparison, other F protein fusion inhibitors, such as BMS-433771 and RFI-641, were not effective when used therapeutically in the murine model [13,26], although RFI-641 showed efficacy in the African Green Monkey when administered in this manner [27]. …”

Section: Discussionmentioning

confidence: 88%

Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model

Olszewska¹,

Ispas²,

Schnoeller³

et al. 2010

Eur Respir J

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Respiratory syncytial virus (RSV) causes bronchiolitis in young children and common colds in adults. There is no licensed vaccine, and prophylactic treatment with palivizumab is very expensive and limited to high-risk infants. Ribavirin is used as an antiviral treatment in infants and immunosuppressed patients, and its use is limited due to side-effects, toxicity to the recipient and staff, and evidence of marginal clinical efficacy. Therefore, we studied the in vivo kinetics, and the antiviral and protective properties of a novel candidate for RSV disease treatment.The drug is a small molecule (TMC353121) discovered by screening for fusion inhibitory properties against RSV in a cellular infection model. The pharmacokinetics of TMC353121 was studied in BALB/c mice and antiviral effects determined by testing viral loads in lung tissue by quantitative RT-PCR and plaque assay after intranasal RSV infection.At doses of 0.25-10 mg?kg -1 , TMC353121 significantly reduced viral load, bronchoalveolar lavage cell accumulation and the severity of lung histopathological change after infection. Treatment remained effective if started within 48 h of infection, but was ineffective thereafter. Therefore, TMC353121 is a novel potent antiviral drug, in vivo reducing RSV replication and inhibiting consequential lung inflammation, with a great potential for further clinical development.

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“…Recently, several promising small-molecule inhibitors with in vitro and in vivo anti-RSV activity have been identified. These include the disulfonated stilbenes CL387626 and RFI-641 (15,22), the benzimidazole derivative JNJ-2408068 (formerly R-170591) (1,21), the benzotriazole derivative BMS-433771 (4,23), and the triphenol compound VP-14637 (13) (D. C. Pevear et al, Abstr. 40th Intersci.…”

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confidence: 99%

Small Molecules VP-14637 and JNJ-2408068 Inhibit Respiratory Syncytial Virus Fusion by Similar Mechanisms

Douglas

Panis

et al. 2005

Antimicrob Agents Chemother

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Here we present data on the mechanism of action of VP-14637 and JNJ-2408068 (formerly R-170591), two small-molecule inhibitors of respiratory syncytial virus (RSV). Both inhibitors exhibited potent antiviral activity with 50% effective concentrations (EC 50 s) of 1.4 and 2.1 nM, respectively. A similar inhibitory effect was observed in a RSV-mediated cell fusion assay (EC 50 ‫؍‬ 5.4 and 0.9 nM, respectively). Several drug-resistant RSV variants were selected in vitro in the presence of each compound. All selected viruses exhibited significant cross-resistance to both inhibitors and contained various single amino acid substitutions in two distinct regions of the viral F protein, the heptad repeat 2 (HR2; mutations D486N, E487D, and F488Y), and the intervening domain between HR1 and HR2 (mutation K399I and T400A). Studies using [ 3 H]VP-14637 revealed a specific binding of the compound to RSV-infected cells that was efficiently inhibited by JNJ-2408068 (50% inhibitory concentration ‫؍‬ 2.9 nM) but not by the HR2-derived peptide T-118. Further analysis using a transient T7 vaccinia expression system indicated that RSV F protein is sufficient for this interaction. F proteins containing either the VP-14637 or JNJ-2408068 resistance mutations exhibited greatly reduced binding of [ 3 H]VP-14637. Molecular modeling analysis suggests that both molecules may bind into a small hydrophobic cavity in the inner core of F protein, interacting simultaneously with both the HR1 and HR2 domains. Altogether, these data indicate that VP-14637 and JNJ-2408068 interfere with RSV fusion through a mechanism involving a similar interaction with the F protein.

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CL387626 exhibits marked and unusual antiviral activity against respiratory syncytial virus in tissue culture and in cotton rats

Cited by 37 publications

References 14 publications

Oral Efficacy of a Respiratory Syncytial Virus Inhibitor in Rodent Models of Infection

Oral Efficacy of a Respiratory Syncytial Virus Inhibitor in Rodent Models of Infection

Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model

Small Molecules VP-14637 and JNJ-2408068 Inhibit Respiratory Syncytial Virus Fusion by Similar Mechanisms

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